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Science 297 (5589): 2048-2051

Copyright © 2002 by the American Association for the Advancement of Science

Macrophage Apoptosis by Anthrax Lethal Factor Through p38 MAP Kinase Inhibition

Jin Mo Park, Florian R. Greten, Zhi-Wei Li, Michael Karin

The bacterium Bacillus anthracis causes the death of macrophages, which may allow it to avoid detection by the innate immune system. We found that B. anthracis lethal factor (LF) selectively induces apoptosis of activated macrophages by cleaving the amino-terminal extension of mitogen-activated protein kinase (MAPK) kinases (MKKs) that activate p38 MAPKs. Because macrophages that are deficient in transcription factor nuclear factor kappa B (NF-kappa B) are also sensitive to activation-induced death and p38 is required for expression of certain NF-kappa B target genes, p38 is probably essential for synergistic induction of those NF-kappa B target genes that prevent apoptosis of activated macrophages. This dismantling of the p38 MAPK module represents a strategy used by B. anthracis to paralyze host innate immunity.

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Activation of liver X receptors and retinoid X receptors prevents bacterial-induced macrophage apoptosis.
A. F. Valledor, L.-C. Hsu, S. Ogawa, D. Sawka-Verhelle, M. Karin, and C. K. Glass (2004)
PNAS 101, 17813-17818
   Abstract »    Full Text »    PDF »
Anthrolysin O and Other Gram-positive Cytolysins Are Toll-like Receptor 4 Agonists.
J. M. Park, V. H. Ng, S. Maeda, R. F. Rest, and M. Karin (2004)
J. Exp. Med. 200, 1647-1655
   Abstract »    Full Text »    PDF »
Rabbit and Nonhuman Primate Models of Toxin-Targeting Human Anthrax Vaccines.
A. J. Phipps, C. Premanandan, R. E. Barnewall, and M. D. Lairmore (2004)
Microbiol. Mol. Biol. Rev. 68, 617-629
   Abstract »    Full Text »    PDF »
Mitogen activated protein kinases as targets for development of novel anti-inflammatory drugs.
M Karin (2004)
Ann Rheum Dis 63, ii62-ii64
   Abstract »    Full Text »    PDF »
Binary Bacterial Toxins: Biochemistry, Biology, and Applications of Common Clostridium and Bacillus Proteins.
H. Barth, K. Aktories, M. R. Popoff, and B. G. Stiles (2004)
Microbiol. Mol. Biol. Rev. 68, 373-402
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Membrane insertion of anthrax protective antigen and cytoplasmic delivery of lethal factor occur at different stages of the endocytic pathway.
L. Abrami, M. Lindsay, R. G. Parton, S. H. Leppla, and F. G. van der Goot (2004)
J. Cell Biol. 166, 645-651
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Mouse Susceptibility to Anthrax Lethal Toxin Is Influenced by Genetic Factors in Addition to Those Controlling Macrophage Sensitivity.
M. Moayeri, N. W. Martinez, J. Wiggins, H. A. Young, and S. H. Leppla (2004)
Infect. Immun. 72, 4439-4447
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Enhancement of Anthrax Lethal Toxin Cytotoxicity: a Subset of Monoclonal Antibodies against Protective Antigen Increases Lethal Toxin-Mediated Killing of Murine Macrophages.
N. Mohamed, J. Li, C. S. Ferreira, S. F. Little, A. M. Friedlander, G. L. Spitalny, and L. S. Casey (2004)
Infect. Immun. 72, 3276-3283
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Anthrax Lethal Toxin Rapidly Activates Caspase-1/ICE and Induces Extracellular Release of Interleukin (IL)-1{beta} and IL-18.
R. Cordoba-Rodriguez, H. Fang, C. S. R. Lankford, and D. M. Frucht (2004)
J. Biol. Chem. 279, 20563-20566
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Crystal structure of the von Willebrand factor A domain of human capillary morphogenesis protein 2: An anthrax toxin receptor.
D. B. Lacy, D. J. Wigelsworth, H. M. Scobie, J. A. T. Young, and R. J. Collier (2004)
PNAS 101, 6367-6372
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Potent inhibitors of anthrax lethal factor from green tea.
I. Dell'Aica, M. Dona, F. Tonello, A. Piris, M. Mock, C. Montecucco, and S. Garbisa (2004)
EMBO Rep. 5, 418-422
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Selective inhibition of anthrax edema factor by adefovir, a drug for chronic hepatitis B virus infection.
Y. Shen, N. L. Zhukovskaya, M. I. Zimmer, S. Soelaiman, P. Bergson, C.-R. Wang, C. S. Gibbs, and W.-J. Tang (2004)
PNAS 101, 3242-3247
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p38{alpha} Mitogen-activated Protein Kinase Sensitizes Cells to Apoptosis Induced by Different Stimuli.
A. Porras, S. Zuluaga, E. Black, A. Valladares, A. M. Alvarez, C. Ambrosino, M. Benito, and A. R. Nebreda (2004)
Mol. Biol. Cell 15, 922-933
   Abstract »    Full Text »    PDF »
Anthrax Lethal Toxin Induces Human Endothelial Cell Apoptosis.
J. E. Kirby (2004)
Infect. Immun. 72, 430-439
   Abstract »    Full Text »    PDF »
Binding of Anthrax Toxin to Its Receptor Is Similar to {alpha} Integrin-Ligand Interactions.
K. A. Bradley, J. Mogridge, G. Jonah, A. Rainey, S. Batty, and J. A. T. Young (2003)
J. Biol. Chem. 278, 49342-49347
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Cutting Edge: Different Toll-Like Receptor Agonists Instruct Dendritic Cells to Induce Distinct Th Responses via Differential Modulation of Extracellular Signal-Regulated Kinase-Mitogen-Activated Protein Kinase and c-Fos.
S. Agrawal, A. Agrawal, B. Doughty, A. Gerwitz, J. Blenis, T. Van Dyke, and B. Pulendran (2003)
J. Immunol. 171, 4984-4989
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The Metalloproteolytic Activity of the Anthrax Lethal Factor Is Substrate-inhibited.
F. Tonello, P. Ascenzi, and C. Montecucco (2003)
J. Biol. Chem. 278, 40075-40078
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A dually active anthrax vaccine that confers protection against both bacilli and toxins.
G.-E. Rhie, M. H. Roehrl, M. Mourez, R. J. Collier, J. J. Mekalanos, and J. Y. Wang (2003)
PNAS 100, 10925-10930
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The KDEL Receptor Modulates the Endoplasmic Reticulum Stress Response through Mitogen-activated Protein Kinase Signaling Cascades.
K. Yamamoto, H. Hamada, H. Shinkai, Y. Kohno, H. Koseki, and T. Aoe (2003)
J. Biol. Chem. 278, 34525-34532
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